The Role of NMDA Receptors in S​chizophrenia

John M. Kane, MD​

Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry, Hofstra North Shore-Long Island Jewish School of Medicine, Uniondale; and Behavior Health Services, North Shore-Long Island Jewish Health System, New Hyde Park, New York

Research into the etiology and pathogenesis of schizophrenia has revealed that a number of receptors, when stimulated or blocked, produce schizophrenia-like symptoms. For example, amphetamine, which increases dopamine production and D2 occupancy, and LSD, which enhances dopaminergic transmission via 5-HT2A receptor blockade, produce psychosis similar to the positive symptoms of schizophrenia.1,2 However, these types of agents do not produce symptoms across all domains, suggesting that other receptor systems are involved. For instance, studies1,3 have shown that administering noncompetitive NMDA receptor antagonists, such as ketamine and PCP, produces symptoms across positive, negative, and cognitive domains, as well as neurologic dysfunction (AV 1).4

The Glutamate Hypothesis

Results from studies using NMDA antagonists have led to the development of the glutamate hypothesis of schizophrenia.4 This hypothesis posits that glutamatergic hypofunction, particularly dysfunctional NMDA receptor-mediated neurotransmission, underlies the pathogenesis of schizophrenia.1,3 (For more information, see “The Glutamate Hypothesis in Schizophrenia.”) Some of the genetic contributions to the etiology of schizophrenia may also support this hypothesis. For example, patients with schizophrenia have been shown to have a greater concentration of susceptibility genes within the glutamate pathways versus the dopamine or GABA pathways5 and to have altered peripheral and central glycine and d-serine levels, which are 2 endogenous amino acids used as co-agonists with glutamate to activate the NMDA receptor site.1 (The role of glycine and d-serine is explained in further detail below.)

Thus, NMDA receptor dysfunction may represent a novel treatment target for patients with schizophrenia that would more fully address all symptom domains of the disorder, as opposed to the current FDA-approved treatments, which focus only on dopamine D2 or serotonin 5-HT antagonism or partial agonism to alleviate positive symptoms.

NMDA Receptor Functioning

Glutamate is the most prominent excitatory neurotransmitter in the brain, and, through ionotropic and metabotropic receptors, it mediates neuropsychological functioning.1 Kainate, AMPA, and NMDA are the 3 types of ionotropic glutamate receptors, and NMDA plays a large role in memory formation, synaptic plasticity, and circuit formation and maturation during brain development.

During the maturation process, or the “critical development window,” NMDA receptors are particularly vulnerable to genetic and environmental risk factors (eg, altered glycine and d-serine levels, glutathione depletion, developmental neurotoxicity, metabolic variations), both of which can cause low NMDA functioning.1,6 As a result, NMDA receptor hypofunction can lead to sensory deficits, generalized cognitive deficits, impaired learning and memory, thought disorder, negative symptoms, positive symptoms, gating deficits, executive dysfunction, and dopamine dysregulation, an established mechanism implicated in the symptoms of psychosis.1

For NMDA receptors to function properly, both a presynaptic and postsynaptic event are required (AV 2). NMDA receptors are permeable to sodium and calcium, but the receptors are blocked by magnesium, which prevents these ions from passing through the receptor. To allow sodium and calcium ions to pass through, an action potential is needed to release glutamate into the synapse and glutamate then binds to the AMPA receptor. The AMPA receptor opens, and an influx of sodium into the postsynaptic neuron causes cellular depolarization, which displaces the magnesium in the NMDA receptor through a process called electrostatic repulsion. At the same time, the glutamate also binds to the NMDA receptor, and for the NMDA receptor to open, a co-agonist such as glycine or d-serine must bind to an allosteric site on the receptor as well. Once the receptor is open and the magnesium has been displaced, calcium and sodium ions can flow into the receptor and potassium can flow out of the receptor. Here, calcium is a secondary messenger that activates several intracellular cascades and affects many downstream neurobiological processes.1 Additionally, NMDA receptors also regulate the downstream release of dopamine and other common neurotransmitters, including glutamate and GABA, which are thought to be involved in the pathophysiology of schizophrenia (AV 3).1

Disturbances at any point in this process could potentially lead to specific NMDA receptor–related impairments or NMDA-mediated neurotransmitter impairments seen in schizophrenia.6 For example, calcium entry into the NMDA receptor initiates long-term potentiation (LTP), a process necessary for memory formation and retention and the basis for synaptic plasticity. Activation of NMDA receptors is necessary for LTP to start but not to continue. Thus, having disturbances in NMDA receptor functioning may explain why patients with schizophrenia have deficits in forming memories but not in retaining them.1,4

Conclusion

NMDA receptor hypofunction provides a potential explanation for the constellation of symptoms of schizophrenia, including positive, negative, and cognitive symptoms, as well as neuropsychological dysfunction. Targeting this neurotransmitter system with pharmacotherapy may help to mediate the downstream release of other neurotransmitters, such as glutamate, GABA, and dopamine, which in turn may moderate the symptoms of schizophrenia.

Clinical Points

NMDA receptor antagonists have been shown to produce positive, negative, and cognitive symptoms as seen in schizophrenia

NMDA receptor hypofunction may represent a novel treatment target for patients with schizophrenia to comprehensively address the range of symptom domains